The Cyclopropane Ring as a Reporter of Radical Leaving-Group Reactivity for Ni-Catalyzed C(sp3)-O Arylation

Article abstract of DOI:10.1021/jacs.0c06904

The ability to understand and predict reactivity is essential for the development of new reactions. In the context of Ni-catalyzed C(sp3)-O functionalization, we have developed a unique strategy employing activated cyclopropanols to aid the design and optimization of a redox-active leaving group for C(sp3)-O arylation. In this chemistry, the cyclopropane ring acts as a reporter of leaving-group reactivity, since the ring-opened product is obtained under polar (2e) conditions, and the ring-closed product is obtained under radical (1e) conditions. Mechanistic studies demonstrate that the optimal leaving group is redox-active and are consistent with a Ni(I)/Ni(III) catalytic cycle. The optimized reaction conditions are also used to synthesize a number of arylcyclopropanes, which are valuable pharmaceutical motifs.

Full text of DOI:10.1021/jacs.0c06904

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Article
The cyclopropane ring as a reporter of radical leaving-
group reactivity for Ni-catalyzed C(sp3)–O arylation
L. Reginald Mills, John Monteith, Gabriel dos Passos Gomes, Alan Aspuru-Guzik, and Sophie A.L. Rousseaux
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06904 • Publication Date (Web): 01 Jul 2020
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Journal of the American Chemical Society
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The cyclopropane ring as a reporter of radical leaving-group reactivity for Ni-
catalyzed C(sp3)–O arylation
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L. Reginald Mills,1 John J. Monteith,1 Gabriel dos Passos Gomes,1,2 Alán Aspuru-Guzik,1,2,3,4 and Sophie
A. L. Rousseaux1,*
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1 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
2 Department of Computer Science, University of Toronto, 214 College St., Toronto, Ontario M5T 3A1, Canada
3 Vector Institute for Artificial Intelligence, 661 University Ave. Suite 710, Toronto, Ontario M5G 1M1, Canada
4 Lebovic Fellow, Canadian Institute for Advanced Research (CIFAR), 661 University Ave, Toronto, ON M5G 1M1, Canada
ABSTRACT: The ability to understand and predict reactivity is essential for the development of new reactions. In the
context of Ni-catalyzed C(sp3)–O functionalization, we have developed a unique strategy employing activated
cyclopropanols to aid the design and optimization of a redox-active leaving group for C(sp3)–O arylation. In this chemistry,
the cyclopropane ring acts as a reporter of leaving-group reactivity, since the ring-opened product is obtained under polar
(2e) conditions, and the ring-closed product is obtained under radical (1e) conditions. Mechanistic studies demonstrate
that the optimal leaving group is redox-active and are consistent with a Ni(I)/Ni(III) catalytic cycle. The optimized reaction
conditions are also used to synthesize a number of arylcyclopropanes, which are valuable pharmaceutical motifs.
Ultimately, more general strategies which employ redox-
active C(sp3)–O leaving groups in Ni catalysis may aid the
rational design of future coupling partners.
Introduction
The design of cross-coupling reactions that enable
functionalization of new coupling handles that are present
in readily available building blocks is of high value since
these tools enable more facile access to important
molecular motifs, especially those prominent in valuable
classes of compounds like pharmaceuticals and
agrochemicals. One significant development in the area of
Ni catalysis is the use of relatively inert C(sp2)–O and
C(sp3)–O bonds as coupling partners, which are derived
from simple alcohols.1 While this strategy has been widely
explored, the overwhelming reactivity regime for the
functionalization of these substrates follows a Ni(0)/Ni(II)
catalytic cycle, which does not utilize the unique redox-
activity and oxidation states of Ni.2 To date, there are very
few examples of redox-active leaving groups which have
been directly functionalized by Ni without the aid of an
external photocatalyst or reductant.3–5 Protocols
employing redox-active alcohol derivatives possess the
advantages of radical chemistry, namely being able to
functionalize activated alcohols without the mechanistic
limitations of two-electron (SN1- and SN2-type)
substitution, and the general ability to perform cross-
coupling reactions under relatively mild conditions.2b
The ability to understand the factors that govern
reactivity and selectivity for specific reaction pathways is
crucial to efficient reaction development. In line with our
group’s interest in the chemistry of cyclopropanol
functionalization6
and
related
Ni-catalyzed
transformations,7 we envisioned a unique strategy for the
C(sp3)–O arylation of cyclopropanols, which may aid in
the understanding and design of redox-active partners for
Ni-catalyzed cross-coupling. Namely, cyclopropyl
electrophiles reveal two-electron versus one-electron
reactivity via the product obtained in a substitution
reaction (Figure 1). When cyclopropyl electrophiles are
treated to two-electron substitution chemistry, the ring-
opened product is typically obtained; concerted
substitutions result in an SN2’ pathway (Figure 1a, top
arrow),8 while SN1 reactions occur via rapid ring-opening
of the cyclopropyl cation9 (Figure 1a, bottom arrow).10,11
Alternatively, cyclopropyl radicals have a lifetime which
allows them to be captured without rupture of the
cyclopropane.12 Thus, the one-electron substitution
process can retain the cyclopropane ring. In the context of
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Page 2 of 12
Ni catalysis, a number of redox-active leaving groups have
(Figure 1, retrosynthesis arrow).19 Further, the arylation of
1
2
3
4
been employed for cyclopropane functionalization,
including iodides,13 bromides,14 N-hydroxyphthalimide
esters (derived from carboxylic acids),15 and pyridinium
salts (derived from cyclopropylamines) (Figure 1b).16–18
these starting materials provides access to desirable
arylcyclopropane derivatives, which are important motifs
in pharmaceuticals20–22 (Figure 1c, bottom right box).
5
6
7
Figure 1. Polar and radical cyclopropane reactivity
a) Polar (2e) substitution pathways give ring-opened products
Results and Discussion
8
9
H
SN2
We began exploring the reactivity of activated
cyclopropanols under Ni-catalyzed Negishi-type
conditions (Table 1), employing an arylzinc reagent
(3 equiv) (prepared from the corresponding Grignard
reagent23), Ni source (10 mol %), and ligand, in 1,4-
dioxane/THF at 23 or 110 ºC for 12 h. A heat-map
representation is employed to demonstrate the leaving
group’s propensity to undergo polar (2e) reactivity with
formation of ring-opened product 2a (red) or radical (1e)
reactivity with formation of ring-intact isomer 3a (green).
It should be noted that the optimal conditions for polar and
SN2’
Y
R
Y
R
H
H
R
Y
Mn
n
+
M
10
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H
inaccessible
for SN2
2e substitution
gives ring-opened
Mn+2
R
Mn
SN1
Y
R
R
R
unstable
b) Redox-active leaving groups for Ni-catalyzed cyclopropane
functionalization
O
R
Ph
Me
N
BF4
Ph
O
N
R
R
R
Br
I
R
O
O
Ph
Arisawa and
Shuto, 2015
Garnsey and
Watson, 2019
Figure 2. Optimization of the leaving groupa
Martin, 2016
Baran, 2016
4-OMePhZnOMe (3 equiv)
Ni (10 mol %), ligand
Ph
Ar
c) Reaction design for Ni-catalyzed C(sp3)–O arylation
Ph
O
Ar
Ph
2a
1,4-dioxane/THF (3:1)
23 or 110 ºC, 12 h
1e product
2e product
Kulinkovich;
protection
3a
ArZnX
cat. Ni
1
O
R
R
(1 equiv)
Ar
+
yield 2a (%) / yield 3a (%)
OLG
Ar
R
R
OR’
Ar = 4-OMePh
readily available
esters
product distribution reflects
leaving group reactivity
polar (2e)
reactivity
O
O O
S
O
O O
S
p-Tol
Me
CF3
1c
Optimal Structure
Arylcyclopropanes in Pharmaceuticals
t-Bu
1d
1a
Me Me
Me
1b
96 / 0b
41 / 0d
3 / 0c
0 / 0c
S
R
Me
96 / 0b
Ph
O
N
O
N
Bz
O
O
O
O
NH
HO2C
Me Me
CO2H
O
O
[redox-active]
[bench-stable]
[odourless]
N
O
O
F
N
OPh
N
N
O
F
1g
1f
Lumacaftor (cystic fibrosis)
(retinoid)
1e
trace / 1c
trace / 1c
0 / 0d (0 / 1)e
S
S
S
N
S
For the Ni-catalyzed C(sp3)–O functionalization
reaction of cyclopropanols, the product distribution would
directly reflect the reactivity of the leaving group (Figure
1c, right arrow), with the arylcyclopropane product being
obtained from a redox-active leaving group. In this sense,
the cyclopropane itself acts as a reporter of two- versus
one-electron reactivity and enables optimization for
desired reactivity. Using this scheme, we discovered that
an N-benzoyl carbamothioate derivative is an optimal
leaving-group structure for C(sp3)–O arylation of
cyclopropanols (Figure 1c, bottom left box). These redox-
active starting materials are bench-stable, odorless, and
prepared in one step from readily available cyclopropanols
Ph
Ph
N
SMe
N
N
Me
Bz
1k
1j
0 / 54d
1h
1i
3 / 29d
0 / 77d
0 / 2b
radical (1e)
reactivity
0 / 1f
aReactions performed on 0.10-mmol scale. Yields determined
by GC-MS using n-dodecane as internal standard. For full
b
details, see SI (Table S1); Using NiCl2(PPh3)2 at 110 ºC;
d
cUsing NiCl2(PCy3)2 at 110 ºC; Using Ni(acac)2•xH2O and
e
bathocuproine (20 mol %) at 23 ºC; Using NiCl2(dme),
dtbbpy (20 mol %), Ru(bpy)3(PF6)2 (1 mol %), blue LEDs,
ArZnCl (2 equiv) and acetone/THF (1:1); fUsing NiCl2(dme)
and neocuproine (20 mol %) at 23 ºC.
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Journal of the American Chemical Society
elimination. Alkoxythiocarbonyl radical 5 is a well-
radical reactivity differ in terms of the Ni source,
established intermediate in Barton–McCombie chemistry.27,28
Further, while leaving group 1k has not been previously
reported for Barton–McCombie deoxygenation, it readily
participates in this reaction, indicating that 1k is redox-active;
in our hands, the deoxygenated product was obtained in 65%
yield, as determined by 1H NMR (Equation S1).
ligand, and reaction temperature. Thus, for simplicity,
Figure 2 explores the trend in reactivity according to
conditions that best represent a leaving group’s reactivity
(see SI for full details). Cyclopropyl tosylate 1a, which is
known to undergo SN2’-type and SN1 reactions,8.10a
selectively yielded the ring-opened product using
NiCl2(PPh3)2 at 110 ºC.24 Under the same conditions,
mesylate 1b also selectively gave the ring-opened isomer.
Less labile leaving groups, esters 1c and 1d, were largely
unreactive under the reaction conditions, however, 2a
could be obtained in trace amounts from 1c using
NiCl2(PCy3)2 at 110 ºC. The first evidence that a redox-
active leaving group could deliver the desired arylated
cyclopropane product was obtained with N-
hydroxyphthalimide oxalate 1e.25,4a While 1e was
unproductive in the presence of Ni alone, 3a was obtained
in 1% yield in the presence of photocatalyst
Ru(bpy)3(PF6)2 and blue LEDs. No ring-opened isomer 2a
was detected in this case. Phenyl carbonate 1f, as well as
imidazole carbamate derivative 1g, each yielded trace
amounts of 3a, however, 2a was also detected in both
cases. Based on our hypothesis that a radical-based
strategy could afford the desired cyclopropane product, we
probed redox-active leaving groups used in Barton–
McCombie deoxygenation reactions.26 Using NiCl2(dme)
and neocuproine at 23 ºC, N-methyl thiocarbamate 1h
delivered cyclopropane 3a in 1% yield with no detectable
amount of 2a. Xanthate 1i and thiocarbonyl imidazolide 1j
both delivered 3a in moderate yield and good selectivity
using Ni(acac)2•xH2O and bathocuproine. Finally, N-
benzoyl carbamothioate 1k gave the desired cyclopropane
in high yield and excellent selectivity. With the exception
of 1e, the reaction mass balance with low-yielding
substrates was unreacted starting material. Notably, the
preference for polar vs. radical reactivity in Figure 2 can
be attributed to the nature of the leaving group, since the
reactions of 1a and 1k under the opposite group’s optimal
ligand set and conditions (bathocuproine and PPh3,
respectively) still gave the same product selectivity, albeit
in much lower yields.
2
3
4
5
6
7
8
9
It is known that thioesters such as 4 are redox-active and
can participate in Barton–McCombie deoxygenations.26a
Thus, we were interested in seeing if 4a could act as an active
coupling partner under our reaction conditions (Figure 3b).
When 4a was exposed to standard reaction conditions, full
conversion was observed, with 82% of 3a being formed, as
determined by GC-MS (Figure 3b). These results
demonstrate that 4 is catalytically competent, and strongly
suggests its role as an intermediate on route to the formation
of 3a.
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Figure 3. Thioester reactivity
a) Formation of thioester side-producta
4-OMePhZnOMe (3 equiv)
Ni(acac)2•xH2O (10 mol %)
S
Ph
O
bathocuproine (20 mol %)
solvent, 23 ºC, 12 h
S
Ph
Ar
Ph
Ph
O
+
N
Ar
Bz
1k
3a
4a
Ar = 4-OMePh
yield 3a (%) yield 4a (%)
solvent
via:
S
1,4-dioxane/THF (3:1)
Ph
78
1
12
66
0
•
O
THF
1,4-dioxane/THF (2:1)b
5
0
b) Catalytic competence of 4a
4-OMePhZnOMe (3 equiv)
Ni(acac)2•xH2O (10 mol %)
bathocuproine (20 mol %)
S
Ph
Ph
O
1,4-dioxane/THF (3:1)
23 ºC, 12 h
OMe
OMe
4a
(1 equiv)
3a
82% (GC-MS)
aSee SI for details; bWithout Ni.
Together, these results suggested that a dual catalytic
cycle was operable under the reaction conditions, with one
Ni(I)/Ni(III) catalytic for the conversion of thiocarbamate 1
to thioester 4, and another for the conversion of 4 to
arylcyclopropane 3. In the first catalytic cycle, Ni(I)–X
intermediate 6 can undergo transmetallation to form Ni(I)–
aryl intermediate 7. Single-electron transfer from 7 to
thiocarbamate 1 will give radical anion 9 and Ni(II)–aryl
cation 8. Fragmentation of 9 will yield thioacyl radical 5.27
Recombination of 5 with 8 will form Ni(III) intermediate 10,
which can undergo reductive elimination to release thioester
4 and regenerate Ni(I)–X intermediate 6. In the second
catalytic cycle, Ni(I)–aryl intermediate 7 can perform single-
electron transfer with 4 to form radical anion 11 and Ni(II)–
aryl cation 8. Fragmentation of radical anion 11 can generate
Under the optimized reaction conditions using substrate
1k, the major side-product is thioester 4a (Figure 3a).
Thioester 4a is not observed in the absence of Ni (Figure 3a,
third entry), and the formation of both 3a and 4a shows a
significant ligand dependence (Table S2). The yield of 4a can
also be increased by changing the reaction solvent (Figure 3a,
second entry). Thioester
recombination of
alkoxythiocarbonyl radical (5),26b followed by reductive
4
likely arises from the
a
Ni–aryl species with an
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Figure 4. Proposed reaction mechanism
1
2
3
4
5
6
7
8
ZnX2
1
X
LnNiIII
•
LnNiI
Ar
R
R
R
Ar
7
12
Ar
S
R
13
ArZnOMe
–ArCOS
3
•
Ph
O
N
Bz
9
LnNi(I)X
LnNi(I)X
LnNiII
LnNiII
Ar
Ar
S
S
R
6
•
6
8
8
9
O
11
Ar
Ar
–NPhBz
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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57
58
59
60
ArZnOMe
R
R
O
4
X
LnNiIII
S
•
O
LnNiI
Ar
5
O
Ar
ZnX2
7
R
10
cyclopropyl radical 12, which will quickly recombine with 8
to form Ni(III) species 13. Then, reductive elimination will
form arylcyclopropane 3 and regenerate Ni(I)–X intermediate
6. Based on our mechanistic studies (Figure 5), it is likely that
the radical anions and Ni(II) cations (9 and 8; and 11 and 8)
are solvent-caged contact-ion pairs.
thiobenzoate (4a) to undergo conversion to cyclopropane
(3a). To gain a better understanding of this mechanism, the
kinetics for fragmentation of a radical anion (11) to form a
cyclopropyl radical (12) and a thiobenzoate anion (14) were
studied computationally, for derivatives with either a 4-
fluorophenyl (X = F, 11b) or 4-methoxyphenyl (X = OMe,
11a) substituent on the thiobenzoate (Figure 6). When the
transition state
Under catalytic conditions, we also noticed a correlation
between the yield of thioester side-product 4 and the
electronic properties of the arylzinc reagent (Figure 5a).29
While the use of the 4-methoxyphenylzinc reagent results in
good yield of cyclopropane (3a) and only 12% yield of the
thioester (4a) (entry 1), using the 4-fluorophenylzinc reagent
results in a more significant 54% yield of the thioester (4b).
This suggests that the thioester (4) is efficiently formed in
both cases, but that the OMe-substituted thioester more
readily goes on to form cyclopropane. To support this
catalytic scenario, we performed crossover experiments
between 4-methoxyphenyl thioester 4a and 4-
fluorophenylzinc chloride, as well as between 4-fluorophenyl
thioester 4b and 4-methoxyphenylzinc chloride (Figure 5b).
Under standard reaction conditions, 4a gave the desired
product 3b in 49% yield,30 with no detectable formation of 4-
methoxyphenyl cyclopropane (3a), as determined by GC-
MS. Alternatively, the crossover experiment with 4-
fluorophenyl thioester 4b gave only a 5% yield of desired
product 3a, with no detectable formation of 4-fluorophenyl
cyclopropane (3b). These results indicate that the 4-
methoxyphenyl thiobenzoate substituent is a competent
leaving group and that the arene found in product 3 comes
from a second equivalent of arylzinc reagent (cf. Table S5).
Figure 5. Reactivity of para-substituted (a) arylzinc reagents
and (b) thioesters with arylzinc reagents
a) Formation of cyclopropane 3 vs. thioester 4 as a function of the
electronic properties of the para-substituted arylzinc reagent
S
ZnOMe
Ph
O
S
[Ni]
Ph
Ar
Ph
Ph
O
+
+
N
std.
cdtns.
Ar
X
X
Bz
3 (%)
4 (%)
1k (1 equiv)
(3 equiv)
Entry
Yield 3 (GC-MS)
Yield 4 (GC-MS)
1
2
OMe (a)
F (b)
78%
10%
12%
54%
b) Arylzinc crossover experiments
4-F-PhZnCl
(2 equiv)
[Ni]
S
Ph
Ph
Ph
O
+
cdtns.
as above
F
OMe
OMe
4a
3b
49%
3a
<5%
4-OMe-PhZnCl
(2 equiv)
[Ni]
S
Ph
Ph
Ph
O
+
cdtns.
as above
F
OMe
F
4b
3a
5% (GC-MS)
3b
<5%
This difference in reactivity between electron-rich and -
deficient thiobenzoates was intriguing since we reasoned that
fragmentation radical anion (11) should be facilitated by a
more electron-withdrawing substituent that would stabilize
the anionic intermediate and promote conversion of the
thiobenzoate ester. Yet, this was at odds with the preference
of the apparently more electron-rich 4-methoxyphenyl
energies for fragmentation were compared, the barrier for
fragmentation of the radical anion with a 4-methoxy
substituent (X = OMe, 11a) was 2.1 kcal/mol lower than that
for fragmentation of the 4-fluoro derivatives (X = F, 11b),
consistent with experimental observations (Figure 5). This
energy difference can be attributed to a key stabilizing effect
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of the O–CH3 antibonding orbital, which can accept negative
by Walborsky that the rate of reaction within the solvent cage
1
2
3
4
5
6
7
8
charge from the aromatic system via hyperconjugation31
(ꢀꢀꢀ → ꢁꢀ∗ꢁ = 2.3 kcal/mol).32 This can be observed in the
calculated geometry of the OMe group (Figure 6, top right
structure) does not lie in plane, the usual geometry where the
p-type lone pair overlaps with the aromatic π-system. Rather,
the OMe group adopts an orthogonal geometry to enable
overlap of the O–CH3 antibonding orbital with the π-system.
Thus, in this case, the OMe group acts not as an electron-
donating group, but as a charge-stabilizing substituent,
resulting in a lower barrier for fragmentation when compared
to the F group. The chameleonic nature of methoxy
substituents in the stabilization of negative charge has been
is faster than the rate of inversion, and that the configuration
of the cyclopropane should remain largely intact.12 For this
reaction, the in-cage reaction would be recombination of the
Ni(II)–cyclopropyl radical pair to form a Ni(III) intermediate
(Figure 7b, right bracket).39–41 The remaining mass balance in
these reactions is the thioester intermediate (4). While the
yields for the reactions using these multisubstituted
cyclopropanes are lower than those for 1-arylcyclopropanes,
increased conversion to the product can be achieved using
higher catalyst loading (20 mol %) and 4 equiv of arylzinc
reagent (trans-17, 28%).
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11
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Figure 7. Stereochemical outcome of the reaction
a) Loss of enantiomeric excess
previously documented.33,34
4-OMePhZnOMe (3 equiv)
Figure 6. Kinetic profile for fragmentation of radical anion
6. Level of theory: (SMD=1,4-dioxane)/UωB97X-D2/6-
311++G(2d,p)
Ni(acac)2•xH2O (10 mol %)
bathocuproine (20 mol %)
Me
S
Me
Ar
Ph
O
N
MgCl2 (2 equiv)
1,4-dioxane/THF (3:1)
23 ºC, 12 h
2-Np
Bz
16, 7%
racemic
Ar = 4-OMePh
15
83% ee
b) Diastereospecific arylation
4-OMeZnOMe
S
Ph
Ar
LnNiII
+
Ph
[Ni]
Ph
O
N
cdtns.
R
R
as above
R1
R2
Bz
•
cis-19/cis-20
R = Et, cis-17
R = Me, cis-18
18%, >20:1 d.r. (R = Et)
20%, >20:1 d.r. (R = Me)
Ph
4-OMeZnOMe
S
Ph
Ar
Ph
[Ni]
Ph
R1
R2
NiIIILn
Ph
O
N
cdtns.
as above
Et
Et
Bz
X = F (b)
X = OMe (a)
trans-19
14%, >20:1 d.r.
28%, >20:1 d.r.a
trans-17
aUsing 20 mol % Ni and 4 equiv 4-OMeZnOMe.
Finally, we explored the scope of cyclopropanes
accessible under the optimized conditions (Table 1).42
Electron-rich (3c–3e) and electron-deficient (3f, 3g)
cyclopropanols are compatible substrates. Radical-stabilizing
π-susbtituents (3h, 3i) work efficiently. Bicyclic
cyclopropanes (3j–3l) can also be accessed in moderate
yields. While alkyl-substituted cyclopropanols are less
efficient substrates, conversion to the desired product can be
improved using greater amounts of arylzinc reagent and
higher catalyst loading (3m).
S
•
S
Ph
O
∆∆Grxn = 2.3
•
+
Ph
O
Ar
11
12
14
X
With this data in hand, experiments were performed to
validate the role of radical intermediates. First,
enantioenriched thiocarbamate substrate 15 was exposed to
standard reaction conditions, and product 16 was obtained as
a racemic mixture (Figure 7a). This is consistent with
fragmentation to generate a benzylic radical.35 We also
submitted diastereomers cis-17, cis-18, and trans-17 to the
standard reaction conditions (Figure 7b). All of these
reactions yielded the arylated cyclopropane with complete
diastereospecificity, and no detection of the opposite
stereoisomer. It is known that cyclopropyl radicals have a
barrier to inversion, and that stereochemistry is maintained in
cases of radical disproportionation36 and in solvent-caged
recombination with transition metal catalysts.37,38 Namely,
for solvent-caged cyclopropyl radicals, it has been estimated
With respect to the arylzinc reagent, alkoxy- and amino-
substituted arenes (3n–3p) can be employed, as well as
heteroaromatic arenes (3q–3s). For incompatible arylzinc
reagents, the major product is thioester 4, and poor
conversion to cyclopropane is achieved (see Table S8).43 We
hypothesize that viable arylzinc reagents have some charge-
stabilizing property which assists with fragmentation (Figure
6). For electron-neutral (hetero)arylzinc reagents (3t–3w)
that are not viable under standard reaction conditions, the
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desired product can be obtained if the 4-methoxyphenyl prediction of reactivity of activating groups in Ni catalysis,
1
2
3
4
5
6
7
8
thioester (4a) is used as the redox-active starting material
and the development of future cross-coupling reactions. Our
results also demonstrate the possibility of extremely short
lifetimes for some radicals, sometimes shorter than the time
required to activate classical “radical clocks”.39a Our group is
actively exploring Ni-catalyzed functionalization of other
alcohol derivatives, using the lessons learned in this
chemistry to facilitate leaving group design. We will also
soon disclose the scope and mechanistic insights of a Ni-
catalyzed ring-opening arylation reaction to form product 2.
instead.
Table 1. Scope of the reactiona
ArZnOMe (3 equiv)
Ni(acac)2•xH2O (10 mol %)
bathocuproine (20 mol %)
S
R2
O
R2
Ar
R1
Ph
R1
N
MgCl2 (2 equiv)
1,4-dioxane/THF (3:1)
23 ºC, 12 h
Bz
1
(1 equiv)
3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cyclopropanols
OMe
O
S
COMPUTATIONAL DETAILS
for
Ar =
Ar
Ar
Ar
OMe
All DFT calculations were carried out with the Gaussian 16
software package.44 Initial geometries were generated with
openbabel45 from their SMILES strings, and pre-optimized
with Grimme’s xtb 6.2.3.46 The initial xtb-optimized
geometries were used for a thorough conformer search with
Grimme’s crest.47 Further geometry optimizations were
performed with (SMD48=1,4-dioxane) for solvation
corrections and the unrestricted wB97X DFT functional49
employing the 6-311++G(2d,p) basis set for all atoms.
Grimme’s D2 empirical dispersion corrections50 were also
included. The integration grid emplowed was of 175,974
points for the first-row atoms and of 250,974 points for the
atoms in the second and later rows). Frequency calculations
were performed to confirm if a structure is a ground or
transition state. Paton’s GoodVibes51 was used to obtain
quasi-harmonic corrections to Gibbs Free Energies (via
quasi-harmonic corrections to both entropy and enthalpy,
defaulting to the Grimme method for entropy and the Head-
Gordon enthalpy correction approach).
3c, 66%
3d, 72%
3e, 53%
Me
Me
CF3
Cl
Ph
Ar
Ar
Ar
Ar
Me
3f, 45%
3g, 39%
3h, 96%
3i, 72%
H
H
H
O
Bn
Ar
Ar
Ar
Ar
3m, 33%b
3j, 60%
3k, 52%
3l, 43%
Arylzinc reagents
Ph
Ph
Ph
Ph
OMe
OMe
Bn
N
OMe
OTBS
Bn
3p, 53%
3a, 67%
3n, 60%
3o, 60%
Ph
Ph
Me
Ph
N
N
N
Natural Bond Orbital52 (NBO) analyses were performed with
NBO7 as linked to Gaussian 16. They were used to gauge the
magnitude of the hyperconjugative interactions in the
presented systems. CYLView53 was used to render the
molecules.
N
N
N
N
N
Bn
S
3q, 32%
3r, 57%
3s, 47%
Ph
Ph
Ph
Ph
S
O
3t, 74%c
3u, 36%c
3v, 49%c
3w, 43%c
ASSOCIATED CONTENT
aReactions performed on 0.10–0.40 mmol scale; bUsing
ArZnCl (4 equiv), Ni(acac)2•xH2O (20 mol %), and
bathocuproine (40 mol %); cUsing 4a instead of 1, ArZnCl (2
equiv), and without MgCl2. For supplementary examples and
lower-yielding substrates, see Table S8.
Reaction optimization tables, mechanistic and stoichio-
metric studies, synthetic procedures, characterization data,
and computational details (PDF)
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
Conclusion
*E-mail: sophie.rousseaux@utoronto.ca.
ORCID
In conclusion, we have discovered a new redox-active
leaving group to enable the Ni-catalyzed C(sp3)–O arylation
of cyclopropanols. The discovery of this leaving group was
accomplished using a unique optimization strategy in which
the redox-activity of the leaving group was reflected in the
distribution of ring-closed versus ring-opened products. We
believe the optimization strategy used here may aid the
Sophie A. L. Rousseaux: 0000-0002-6505-5593
L. Reginald Mills: 0000-0002-6329-2368
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Journal of the American Chemical Society
Catalyzed Cross- Coupling Reactions. Trends Chem. 2019, 1,
830–844.
Gabriel dos Passos Gomes: 0000-0002-8235-5969
1
2
3
4
5
Alán Aspuru-Guzik: 0000-0002-8277-4434
Notes
3. For a Ni-catalyzed protocol employing aryl carbonates:
Oelke, A. J.; Sun, J.; Fu, G. C. Nickel-Catalyzed
Enantioselective Cross-Couplings of Racemic Secondary
Electrophiles That Bear an Oxygen Leaving Group. J. Am.
Chem. Soc. 2012, 134, 2966–2969.
No competing financial interests have been declared.
6
4. For protocols employing redox-active activating groups
for alcohols and Ni catalysis: Oxalate: (a) Zhang, X.;
MacMillan, D. W. C. Alcohols as Latent Coupling Fragments
for Metallaphotoredox Catalysis: sp3–sp2 Cross-Coupling of
Oxalates with Aryl Halides. J. Am. Chem. Soc. 2016, 138,
13862–13865; Xanthate: (b) Vara, B. A.; Patel, N. R.;
Molander, G. A. O-Benzyl Xanthate Esters under
Ni/Photoredox Dual Catalysis: Selective Radical Generation
and Csp3–Csp2 Cross-Coupling. ACS Catal. 2017, 7, 3955–
3959; Methyl oxalate: (c) Ye, Y.; Chen, H.; Sessler, J. L.;
Gong, H. Zn-Mediated Fragmentation of Tertiary Alkyl
Oxalates Enabling Formation of Alkylated and Arylated
Quaternary Carbon Centers. J. Am. Chem. Soc. 2019, 141,
820–824.
5. For select protocols employing a redox-active alcohol
activating group and transition metal catalysis: (a) Zhu, L.;
Liu, S.; Douglas, J. T.; Altman, R. A. Copper-Mediated
Deoxygenative Trifluoromethylation of Benzylic Xanthates:
Generation of a C–CF3 Bond from an O-Based Electrophile.
Chem. Eur. J. 2013, 19, 12800–12805; (b) Chenneberg, L.;
Baralle, A.; Daniel, M.; Fensterbank, L.; Goddard, J.-P.;
Ollivier, C. Adv. Synth. Catal. 2014, 356, 2756–2762.
6. Mills, L. R.; Barrera Arbelaez, L. M.; Rousseaux, S. A.
L. Electrophilic Zinc Homoenolates: Synthesis of
Cyclopropylamines from Cyclopropanols and Amines. J. Am.
Chem. Soc. 2017, 139, 11357–11360.
7
8
9
ACKNOWLEDGMENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We thank NSERC (Discovery Grants and Canada Research
Chair programs), the Canada Foundation for Innovation
(Project No. 35261), the Ontario Research Fund,
Kennarshore Inc., and the University of Toronto for generous
financial support of this work. We also acknowledge the
Canada Foundation for Innovation (Project No. 19119) and
the Ontario Research Fund for funding the Centre for
Spectroscopic Investigation of Complex Organic Molecules
and Polymers. L.R.M. thanks NSERC for a graduate
scholarship (PGS D). J.J.M. thanks NSERC for a graduate
scholarship (CGS M) and the University of Toronto for a
doctoral scholarship (FAST). Dr. Jack Sheng (University of
Toronto) is thanked for assistance with NMR studies.
Nicholas Michel (University of Toronto) is thanked for
valuable mechanistic insight. G. P.
G
gratefully
acknowledges NSERC for the Banting Postdoctoral
Fellowship. A. A-G. thanks Anders G. Frøseth for his
generous support. A. A.-G. also acknowledges the generous
support of Natural Resources Canada and the Canada 150
Research Chairs program, Tata Steel, and the Office of Naval
Research. We thank Compute Canada for computational
resources. DFT and NBO computations were performed on
the niagara supercomputer at the SciNet HPC Consortium.
SciNet is funded by: the Canada Foundation for Innovation;
the Government of Ontario; Ontario Research Fund -
Research Excellence; and the University of Toronto. Dr.
Louis-Charles Campeau and Michael S. West are thanked for
a critical reading of this manuscript.
7. Mills, L. R.; Zhou, C.; Fung, E.; Rousseaux, S. A. L. Ni-
Catalyzed
β-Alkylation
of
Cyclopropanol-Derived
Homoenolates. Org. Lett. 2019, 21, 8805–8809.
8. Quan, L. G.; Lee, H. G.; Cha, J. K. Acid- and Pd(0)-
Catalyzed Ring Opening of 1-(1-Cycloalkenyl)cyclopropyl
Sulfonates. Org. Lett. 2007, 9, 4439–4442.
9. G. Boche, H. M. Walborsky, Cyclopropane Derived
Reactive Intermediates (Eds.: S. Patai, Z. Rappoport), Wiley,
Chichester, 1990, pp. 117–173.
10. Select examples: (a) DePuy, C. H.; Schnack, L. G.;
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Synthesis of Cyclopropyl Ethers and Cyclopropanols by
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34. The chameleonic behavior of σ-acceptors involved in
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demonstrated on: (a) the synthesis of poly(aryl thioesteres):
Park, N. H.; Gomes, G. P.; Fevre, M.; Jones, G. O.; Alabugin,
I. V.; Hedrick, J. L. Organocatalyzed Synthesis of
Fluorinated Poly(aryl thioethers). Nat. Commun. 2017, 8,
166, doi: 10.1038/s41467-017-00186-3. (b) the cyclization of
enediynes Peterson, P.; Shevchenko, N.; Breiner, B.;
Manoharan, M.; Lufti, F.; Delaune, J.; Kingsley, M.; Kovnir,
K.; Alabugin, I. V. Orbital Crossings Activated Through
Electron Injection: Opening Communication between
Orthogonal Orbitals in Anionic C1-C5 Cyclizations of
Enediynes. J. Am. Chem. Soc., 2016, 138, 15617
Different Role of Salt in the Cross-Coupling of Arylzincs
From That Seen With Alkylzincs. Angew. Chem. Int. Ed.
2014, 53, 4386–4389 and references cited therein.
24. It is currently unknown what the mechanism of
formation for this product is, though we believe SN2’-type
and SN1-type mechanisms are likely possibilities.
25. (a) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E.
Direct Construction of Quaternary Carbons from Tertiary
Alcohols via Photoredox-Catalyzed Fragmentation of tert-
Alkyl N-Phthalimidoyl Oxalates. J. Am. Chem. Soc. 2013,
135, 15342–15345; (b) Pratsch, G.; Lackner, G. L.; Overman,
L. E. Constructing Quaternary Carbons from N-
(Acyloxy)phthalimide Precursors of Tertiary Radicals Using
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27. (a) Bachi, M. D.; Bosch, E. Synthesis of α-alkylidene-
γ-lactones by intramolecular addition of alkoxycarbonyl free-
radicals to acetylenes. Tetrahedron Lett. 1986, 27, 641–644;
(b) Nozaki, K.; Oshima, K.; Utimoto, K. Synthesis of
lactones by intramolecular addition of alkoxythiocarbonyl
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(e) Bachi, M. D.; Bosch, E. Free Radical Cyclization of
Thionocarbonic Acid Derivatives of 4-Phenyl-3-butenol. A
New Route to Thionolactones. J. Org. Chem. 1989, 54, 1234–
1236; (f) Iwasa, S.; Yamamoto, M.; Kohmoto, S.; Yamada,
K. Synthesis of thionolactones from homoallylic xanthates. J.
Chem. Soc., Perkin Trans. 1 1991, 1173–1176; (g) Iwasa, S.;
Yamamoto, M.; Kohmoto, S.; Yamada, K. Tandem radical
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Zard, S. Z. Factors Affecting the Relative and Absolute Rates
of β-Scission of Alkoxythiocarbonyl Radicals and
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35. The corresponding thioester was also obtained in 12%
isolated yield. Other side-products include vinylnaphthalene,
resulting from β-hydride elimination prior to reductive
elimination, which was present in 1% yield by 1H NMR, and
4-methoxybenzophenone and 4,4’-dimethoxybenzophenone,
whose yields weren’t determined.
36. Walborsky, H. M.; Chen, C.-J. Cyclopropanes. XXIX.
The
Stereochemistry
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1-Methyl-2,2-
diphenylcyclopropyl Radical in and out of Solvent Cage. J.
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37. (a) Walborsky, H. M.; Allen, L. E. The Stereochemistry
of
Tris(triphenylphosphine)rhodium
Chloride
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5465–5468; (b) Miura, T.; Makamura, T.; Stewart, S. G.;
Nagata, Y.; Murakami, M. Synthesis of Enantiopure C3-
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open chemical toolbox. J. Cheminf., 2011, 3, 33; (b) The
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38. Short-lived non-cyclopropyl radical intermediates can
also maintain stereochemistry: (a) Bartlett, P. D.; McBride, J.
M. Configuration, conformation and spin in radical pairs.
Pure Appl. Chem. 1967, 15, 89–108; (b) Kopecky, K. R.;
Gillan, T. Thermal decomposition of optically active
46. xtb
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S.; Grimme, S. GFN2-xTB—An Accurate and Broadly
Parametrized Self-Consistent Tight-Binding Quantum
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39. The rate of inversion for 1-methylcyclopropyl radical is
2.1 × 108 s−1, and the barrier to inversion increases with
substituent size. In comparison, rate of diffusion from the
solvent cage is much faster, estimated at 1011 s−1: (a)
Johnston, L. J.; Ingold, K. U. Kinetics of cyclopropyl radical
reactions. 2. Studies on the inversion of cyclopropyl and 1-
methylcyclopropyl radicals and on the kinetics of some
addition and abstraction reactions of 1-methylcyclopropyl
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108, 2343–2348; (b) S. W. Benson, Foundations of Chemical
Kinetics. McGraw-Hill, New York, 1960.
40. We estimate that the rate of in-cage radical rebound
would be faster than the rate of diffusion, which is therefore
faster than the rate of inversion for the cyclopropyl radical.
At this rate of radical recombination, other radical clocks
would not be informative. The rate of ring-opening of
cyclopropylcarbinyl radical is 1.3 × 108 s−1, and the rate of
C(sp3) radical 5-exo-trig cyclization is 1.0 × 105 s−1, which is
slower for benzylic C(sp3) radicals: (a) Griller, D.; Ingold, K.
U. Free-radical clocks. Acc. Chem. Res. 1980, 13, 317–323;
(b) Radical Reactions in Organic Synthesis. Zard, S. Z.
Oxford: Oxford University Press, 2003.
41. Performing the standard reaction in the presence of 1
equiv of a radical trap like styrene or benzyl acrylate resulted
in no detectable formation of a radical adduct, consistent with
radical intermediates not escaping the solvent cage (Table
S10). Performing the reaction in the presence of 1 equiv
TEMPO shut down the reaction.
9
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localized molecular orbitals. J. Chem. Phys., 1985, 83, 1736–
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53. CYLview, 1.0b; Legault, C. Y., Université de
Sherbrooke, 2009 (http://www.cylview.org).
42. As an additive, MgCl2 (2 equiv) was empirically found
to help with reproducibility across batches of arylzinc
reagent, since zinc(II) halides promoted cleavage of the N–
benzoyl group to form 4-methoxybenzophenone, and which
side-reaction could be slightly retarded with the addition of
MgCl2 (cf. Table S3, entries 9 and 14).
43. The major side-products in this reaction are the ketone
resulting from oxidative addition of the N–Bz bond, the
ketone resulting from double addition into the carbamate
followed by hydrolysis, as well as thioester 4 (see
optimization tables in SI for side-product yields).
44. Gaussian ‘16, Revision C.01, full reference in the ESI.
45. (a) O’Boyle, N. M.; Banck, M.; James, C. A.; Morley,
C.; Vandermeersch, T.; Hutchison, G. R. Open Babel: An
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